Role of SIRT3 in the regulation of Gadd45α expression and DNA repair in β-cells

TL;DR

This study shows that SIRT3, not SIRT1, is essential for DNA repair in β-cells by regulating Gadd45α expression.

Contribution

The paper identifies SIRT3 as the key regulator of Gadd45α and DNA repair in β-cells, correcting earlier assumptions about SIRT1.

Findings

SIRT3 knockdown reduces nitric oxide-stimulated Gadd45α mRNA in β-cells and rat islets.

SIRT3 inhibition increases FoxO1 acetylation and impairs DNA repair in response to nitric oxide.

SIRT3 is localized in the nucleus of insulin-containing cells and regulates FoxO1-dependent DNA repair.

Abstract

In previous studies, we have shown that growth arrest and DNA damage (Gadd) 45α is required for the repair of nitric oxide-mediated DNA damage in β-cells. Gadd45α expression is stimulated by nitric oxide and requires forkhead box protein (Fox) O1 and NAD+-dependent deacetylase activity. Based on inhibitor studies, we attributed this activity to Sirtuin (SIRT)1; however, the inhibitors used in this previous study also attenuate the deacetylase activity of SIRT2, 3, and 6. We now provide experimental evidence that SIRT1 is dispensable for β-cell expression of Gadd45α and that the mitochondrial localized isoform SIRT3, is required for DNA repair in β-cells. We show that siRNA knockdown of Sirt3 attenuates nitric oxide-stimulated Gadd45α mRNA accumulation in both wildtype and Sirt1−/− INS 832/13 cells as well as isolated rat islets and that SIRT3 inhibition increases FoxO1 acetylation and attenuates DNA repair in response to nitric oxide. While SIRT3 is predominantly localized to mitochondria, a small fraction is localized in the nucleus of insulin-containing cells and functions to participate in the regulation of FoxO1-dependent, nitric oxide-stimulated DNA repair.

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